This is a renewal of a project that has enrolled 570 subjects, including 410 depressed elderly patients and 160 non-depressed elderly controls over the past ten years. Over the next five years we will follow 285 active subjects, including 188 patients and 97 controls, with a focus on genetic and post-mortem neuroanatomical correlates of mood and cognition. These subjects are currently being followed in the current study, and no new subjects will be added. Analyses will be performed on all 570 subjects who have been enrolled. Detailed psychosocial, functional, clinical, psychiatric, medical, neurological, and cognitive assessments will continue to be obtained at defined points during follow-up. At least two brain MRI studies will have been performed on all subjects at two year intervals;the existing MRI data will be used in longitudinal analyses as well. The principal outcome measures are trajectory of mood and cognition and on post-mortem neuroanatomical and neuropathological brain changes. The analysis plan focuses on examination of risk for recurrence and chronicity of depression and risk for cognitive decline and later dementia using the following independent variables: change in fronto-striatal lesion burden, change in hippocampal volume, genetic loci (e.g., APOE, TPH-2, and 5HTTLPR), and depression course. The project will preserve past methodological advances by combining psychiatric assessments with psychosocial and psychobiological perspectives. In a study design that employs carefully defined treatment protocols, we will test specific hypothesis regarding mood outcomes and cognitive decline and dementia. A new key feature will be examination of post-mortem brain changes, specifically prefrontal cortex pyramidal cell density and blood vessel density and size. It is expected that the results from this study will clarify the relationship between depression and dementia in the elderly. It will also add to the literature on genetic factors and the long-term outcome of depression in a clinical setting. Ultimately it will advance our understanding of the biology of late life depression. It should also aid in the clinical management of geriatric depression, shedding light on the prognosis for cognitive outcomes of late life depression, as well as for long-term recovery and remission of depression symptoms. Finally, it will be the first prospective longitudinal study in depression to correlate clinical in vivo data on well characterized patients with subsequent post-mortem morphometric analyses.